Myotonic dystrophy (DM or Steinert's disease) is a multisystemic, dominantly inherited disorder often characterized by myotonia or delayed muscle relaxation due to repetitive action potentials in myofibers, and muscle degeneration. Manifestations of DM may also include heart block, ocular cataracts, hypogonadism, and nervous system dysfunction. For example, DM patients often suffer from cardiac conduction defects, smooth muscle involvement, hypersomnia, cataracts, abnormal glucose response, and, in males, premature balding and testicular atrophy. Myotonic dystrophy is the most common muscular dystrophy of adults for which there are no effective therapies.
Myotonic dystrophy type 1 is an RNA-dominant disease caused by abnormal transcripts of the DMPK (dystrophia myotonica protein kinase) gene. The DMPK is a protein expressed by four different mRNA splice variants in skeletal muscle, heart and brain. See, e.g., Brook, 1992, Cell, 68(4):799-808; Mahadevan, 1992, Science, 255(5049): 1253-55; Fu, 1992, Science, 255(5049): 1253-55; Tsilfidis, 1992, Nat. Genet., 1(3): 192-195. DM1 patients have trinucleotide repeat expansions in the 3′-untranslated region, leading to mRNA transcripts with long region of CUG repeats (e.g., greater than 50 to 3000 repeats in afflicted patients). These CUG expanded transcripts aggregate in the nucleus and form RNA foci that have, at least, the following deleterious effects on certain splicing regulatory proteins: deplete muscleblind protein (MBNL1) and misregulate CUGBP Elav family member 1 (CELF1).